1. Field of the Invention
The present invention is broadly directed to methods for inhibiting T cell or B cell activation, proliferation, and differentiation, especially activation, proliferation, and differentiation events associated with autoimmune diseases, and for inhibiting production of autoimmune antibodies. The present invention is particularly directed to the use of a particular class of isozyme selective Protein Kinase C (PKC) inhibitors for treating autoimmune diseases and disorders accompanied by undesired T cell or B cell reactivity.
2. Description of Related Art
The development of immunologic responsiveness to self is called autoimmunity and reflects the impairment of self-tolerance. Immunologic, environmental, and genetic factors are closely interrelated in the pathogenesis of autoimmunity. The frequency of autoimmune antibodies (autoantibodies) in the general population increases with age, suggesting a breakdown of self-tolerance with aging. Autoimmune antibodies (autoantibodies) also may develop as an aftermath of tissue damage. The spectrum of autoimmune disorders ranges from thyroiditis, which is organ specific, to systemic lupus erythematosus, which is characterized by an array of autoimmune antibodies (autoantibodies) to cell and tissue antigens.
The development of autoimmunity usually involyes the breakdown or circumvention of self-tolerance. The potential for the development of autoimmune antibodies (autoantibodies) probably exists in most individuals. For example, normal human B cells are capable of reacting with several self-antigens, e.g., thyroglobulin, but are suppressed from producing autoimmune antibodies (autoantibodies) by one or more tolerance mechanisms. Precommitted B cells in tolerant individuals can be stimulated in several ways. For example, tolerance involving only T cells, induced by persistent low levels of circulating self-antigens, may breakdown in the presence of substances such as endotoxin. Such substances stimulate the B cells directly to produce autoimmune antibodies (autoantibodies). Another tolerance mechanism involves suppressor T cells. A decrease in suppressor T cell activity therefore may also lead to production of autoimmune antibodies (autoantibodies).
Studies have shown that mouse B-1 B lymphocytes produce many of IgM autoimmune and anti-idiotype antibodies such as cold hemagglutinins, cytosketelal antibodies, and rheumatoid factor (Hayakawa et al., 1984, Proc. Natl. Acad. Sci. U.S.A. 81:2494; Herzenberg et al., 198, Immunological. Rev. 93:81). It has been demonstrated that overexpression of B-1 B lymphocytes in preclinical models such as the New Zealand Black (NZB) and motheaten viable mice strains is associated with autoimmune diseases (Hayakawa et al., 1983, J. Exp. Med. 161:1554; Herzenberg et al., 1986, Immunological. Rev. 93:81). Human B cells corresponding to the mouse B-1 B lymphocyte have also been implicated in the production of a variety of human autoimmune antibodies (Plater-Zyberk et al., 1985. Arth. Rheum. 28: 971). Thus, overexpression or activation of B-1 B lymphocyte-like cells is associated with disease states related to overproduction of IgM and certain autoimmune disorders.
Cross linking the B cell receptor leads to activation of phospholipase C and production of diacylglycerol. Diacylglycerol induced activation of the conventional and novel members of the PKC gene family is suspected to be involved in mediating certain B cell responses (Baixeras et al., 1993, Immunol. Rev. 132:5). Targeted disruption of one member of the PKC gene family, the .beta. isoform, produces an immunologically distinct phenotype (Leitges et al., 1996, Science 273:788). Transgenic mice lacking the gene for producing PKC-.beta. demonstrate reductions in B-1 B lymphocyte number, IgM and IgG3 serum levels, a reduction in immunoglobulin production in response to T cell independent antigen challenge, and a blunted primary response to T cell dependent antigen challenge (Leitges et al., 1996). Thus, protein kinase C-.beta. is implicated in modulating B-1 B lymphocyte function and IgM/IgG3 production.
In another preclinical model, PKC-.beta. was selectively overexpressed in T lymphocytes using a Ick promoter (Snyder & Finn , 1997, J. Allergy Clin. Immunol. 99:S307). Transgenic animals carrying the PKC-.beta. gene under the control of the distal lck promoter developed a lymphoproliferative disease that became more severe with aging. This result suggests that PKC-.beta. may be involved in T cell activation and proliferation as well.
Presently available treatments for autoimmune diseases and disorders are scarce and not completely effective. There remains a need in the art to develop more ways to treat autoimmune diseases.